Burn injuries and soft tissue infections infrequently result in amputation; however, the prognostic indicators of lower limb amputation are not well characterized by current literature. Several other studies have estimated the prevalence of amputation to be between 1.8-5.8% in burn patients, but a thorough analysis of past medical history as potential risk factors had not yet been conducted in the United States. Our retrospective study examined the medical charts of 110 patients admitted to the Arizona Burn Center at Maricopa Medical Center between 2000 and 2016 with varying levels of lower limb amputation due to either a burn injury or soft tissue infection. The data was then compared to controls matched for sex, injury mechanism, age, and total body surface area (TBSA) that did not receive an amputation and that were admitted during the same time frame. Statistically significant relative risk factors for amputation included diabetes mellitus, hypertension, smoking history, alcohol abuse, and liver disease, each of which increased risk four to five times over matched controls. Interestingly, all these conditions negatively impact the circulatory system, leading to blood vessel damage, difficulties with wound healing, and increased risk for infection. As the prevalence of obesity and cardiovascular disease increases in the United States’ population, risk factors such as diabetes and hypertension are projected to affect more individuals than ever before. By demonstrating the increase in risk these conditions have on impacting the likelihood of amputation, this study exemplifies the importance of properly managing cardiovascular diseases to both burn clinicians and prevention campaigns.